About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
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January 20, 2011

Merck's Vorapaxar: Bleeding, Indeed

Posted by Derek

So, as had been suspected, the reason that Merck's thrombin antagonist vorapaxar ran into clinical trouble was excessive bleeding. This is always the first thing to suspect when an anticoagulant has difficulty in human trials.

It's really a delicate balance, the human clotting cascade, and it's all too easy to end up on the wrong side of it. When you think about it, the whole pathway has to be under very tight regulation - I mean, here's the fluid that transports oxygen and nutrients and removes waste. Absolutely crucial to the life of every cell in the body. And here's an option to have that fluid thicken up and turn to jelly, very quickly, and once it happens it can't be reversed. No, you're going to want a lot of safeguards around that switch. But if you lean over too far the other way, well. . .there's a lot of vascular plumbing in the body, and it gets a lot of stress. Leaks and rips are inevitable. You have to have a method for patching holes, and it has to be ready to go everywhere, at all times. Dial it down just a bit too much, and hemorrhages are inevitable. Thus all the different clotting mechanism steps, and the different drugs targeting them.

As Matthew Herper explains at that link above, the prospect for this drug are completely dependent on which side of the line it ends up on. In this patient population, it's already stepped over - another result like this one, and vorapaxar could be completely sunk.

So Merck's vorapaxar failed the current clinical trial because it caused bleeding in the brain. The other trial related to this drug is still on and my question to the experts herein, who follow this site is-going forward how would you address the metrics (dosage etc.) so as not to cause bleeding in other trials. With damage already done, Is Merck taking even bigger risk with this drug? By contrast, Plavix, with all the warnings relatively looks very benign at this point in time and is going to come off the patent soon, anyway. Suffice it to say that the bleeding (pun intended) at Merck has been going on for some time and has to stop!

So in my crude understanding of the physiology here, everything targeting the clotting pathway would lead to bleeding at too high of a dose. So is it possible that they just overshot the dosage they gave patients?

It's important to distinguish inhibition of the clotting cascade from platelet inhibition, which is what vorapaxar is doing. It inhibits thrombin's actions on the receptor PAR1 on platelets (and other cells), but not the formation of fibrin. I thought it strange that the drug name has the same suffix as strict coagulation inhibitors, such as Factor Xa blockers.
Targeting platelets reduced the risk of arterial thrombosis without a substantial risk of bleeding, but the bleeding risk is hard to eliminate completely. With pretty effective drug combinations in the market already, showing an additional benefit with little risk is tough.
The problem may well be the dose, not just of vorapaxar, but the combined dose of all antiplatelets in patients in the trials. There are good reasons to use combination antiplatelet therapy (aspirin, clopidogrel (plavix) and vorapaxar all inhibit different pathways of platelet activation) but this is difficult to get right in a one-shot phase III megatrial. No doubt the trial was of vorapaxar plus standard therapy, but the best and safest stratgey might be a reduced dose of aspirin and clopidogrel (which lots of these patients would be on) plus vorapxar. However, this can't be ethically tested in a placebo-controlled trial.

RE Targetting coagulation cascade: Selective factor VIIa inhibitors were supposed to be in principle safer than Xa and thrombin inhibitors because only the tissue factor pathway would be affected. There were seberal programs but as far as I know no VIIa drug on the market yet.

What should also be remembered is how these trials are designed. Although the trials are placebo controlled, everyone is getting standard care in the form of aspirin or clopidogrel (although patients are apparently undergoing randomization on the basis of whether they'll get clopidogrel). So these trials, in essence, ask whether DUAL antiplatelet therapy (vorapaxar PLUS aspirin or clopidogrel) is better than a single, established agent (plus placebo). To my knowledge, these trials will not tell us if vorapaxar is comparable (or noninferior) to either drug (like BMS was able to do in the landmark CAPRIE trial with clopidogrel vs aspirin).

Therefore it's an uphill battle for any company that wants to develop a new preventive antiplatelet. If everybody has to get aspirin or clopidogrel (which they probably do, because it'd be unethical not to give it to them), then the risk of bleeding is going to be multiplied by some factor with dual antiplatelet therapy.

Don't lump all the pathophysiology together. The bleeding was seen in a trial with STROKE patients. Remember at the simplest level there is thrombotic stroke and hemorrhagic stroke. Thrombotic stroke is due to platelet thrombi stopping blood flow from getting to the brain. Like a heart attack, if you react quickly enough, you can minimize damage to your brain. Hemorrhagic stroke is bleeding in the brain. Both end up at the same place: dead brain cells, but get there by different routes. Flipping from thrombotic stroke to hemorraghic stroke is a bad thing: dead brain cells from both routes. That is almost certainly what happened, and is reasonably well known in the medical literature as a risk for all anti-platelet agents. That's why they were so attuned to it, and stopped as soon as they saw it. That's also why they can continue the other trials.